U.S. patent application number 10/442385 was filed with the patent office on 2004-05-27 for inhalation device for producing a drug aerosol.
Invention is credited to Cross, Stephen, Hale, Ron L., Hodges, Craig C., Lloyd, Peter M., Myers, Daniel J., Quintana, Reynaldo J., Rabinowitz, Joshua D., Tom, Curtis, Wensley, Martin J..
Application Number | 20040099266 10/442385 |
Document ID | / |
Family ID | 32329873 |
Filed Date | 2004-05-27 |
United States Patent
Application |
20040099266 |
Kind Code |
A1 |
Cross, Stephen ; et
al. |
May 27, 2004 |
Inhalation device for producing a drug aerosol
Abstract
A device for delivering a drug by inhalation is disclosed. The
device includes a body defining an interior flow-through chamber
having upstream and downstream chamber openings, and a drug supply
unit contained within the chamber for producing, upon actuation, a
heated drug vapor in a condensation region of the chamber. Gas
drawn through the chamber region at a selected gas-flow rate is
effective to form drug condensation particles from the drug vapor
having a selected MMAD between 0.02 and 0.1 MMAD or between 1 and
3.5 .mu.m. A gas-flow control valve disposed upstream of the unit
functions to limit gas-flow rate through the condensation region to
the selected gas-flow rate. An actuation switch in the device
activates the drug-supply unit, such that the drug-supply unit can
be controlled to produce vapor when the gas-flow rate through the
chamber is at the selected flow rate.
Inventors: |
Cross, Stephen; (Alamo,
CA) ; Hodges, Craig C.; (Walnut Creek, CA) ;
Hale, Ron L.; (Woodside, CA) ; Lloyd, Peter M.;
(Walnut Creek, CA) ; Myers, Daniel J.; (Mountain
View, CA) ; Quintana, Reynaldo J.; (Redwood City,
CA) ; Rabinowitz, Joshua D.; (Mountain View, CA)
; Tom, Curtis; (San Mateo, CA) ; Wensley, Martin
J.; (San Francisco, CA) |
Correspondence
Address: |
ALEXZA MOLECULAR DELIVERY CORPORATION
1001 EAST MEADOW CIRCLE
PALO ALTO
CA
94303
US
|
Family ID: |
32329873 |
Appl. No.: |
10/442385 |
Filed: |
May 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60429776 |
Nov 27, 2002 |
|
|
|
60429586 |
Nov 27, 2002 |
|
|
|
Current U.S.
Class: |
128/203.12 ;
128/203.26 |
Current CPC
Class: |
A61M 11/002 20140204;
A61M 11/041 20130101; A61M 11/047 20140204; A61M 15/00 20130101;
A61M 11/042 20140204 |
Class at
Publication: |
128/203.12 ;
128/203.26 |
International
Class: |
A61M 015/00; F23D
011/00 |
Claims
It is claimed:
1. A device for delivering a drug by inhalation or nasally,
comprising a) a body defining an interior flow-through chamber
having upstream and downstream chamber openings, b) a drug supply
unit contained within said chamber for producing, upon actuation, a
heated drug vapor in a condensation region of the chamber adjacent
the substrate and between the upstream and downstream chamber
openings, wherein gas flowed through said chamber region at a
selected gas-flow rate is effective to condense drug vapor produced
by said unit to form drug condensation particles having a selected
MMAD particle size, c) a gas-flow control valve disposed upstream
of said unit for limiting gas-flow rate through said condensation
region to said selected gas-flow rate, as gas is flowed through
said chamber, and d) an actuation switch for actuating said unit,
such that said unit produces vapor with the gas-flow rate through
said chamber controlled to said selected flow rate.
2. The device of claim 1, for use in delivering a drug by
inhalation, wherein said chamber is designed for substantially
laminar air flow within said chamber the selected air-flow rate is
in the range of 4-50 L/min and the condensation particles produced
by condensation of drug vapor are in the range 1-3.5 .mu.m
MMAD.
3. The device of claim 1, for use in delivering a drug by
inhalation, wherein the gas-flow control valve is designed to
produce a selected gas-flow rate effective to produce aerosol
particles in the 20-100 nm size range.
4. The device of claim 1, wherein said gas-flow valve is designed
to limit the rate of air flow through said chamber, as the user
draws air through the chamber by mouth.
5. The device of claim 4, wherein the gas-flow valve includes an
inlet port communicating with said chamber, and a deformable flap
adapted to divert air flow away from said port increasingly, with
increasing pressure drop across the valve.
6. The device of claim 4, wherein said gas-flow valve includes said
actuation switch, with valve movement in response to an air
pressure differential across the valve acting to close said
switch.
7. The device of claim 4, wherein said gas-flow valve includes an
orifice designed to limit airflow rate into said chamber.
8. The device of claim 4, which further includes a bypass valve
communicating with the chamber downstream of said unit for
offsetting the decrease in airflow produced by said gas-flow
control valve, as the user draws air into said chamber.
9. The device of claim 1, wherein the actuation switch includes a
thermistor that is responsive to heat-dissipative effects of air
flow through the chamber to activate said drug-supply unit.
10. The device of claim 9, which further includes a user-activated
switch whose actuation is effective to heat said thermistor, prior
to actuation by the thermistor of the drug-supply unit.
11. The device of claim 1, wherein said actuation switch is
effective to activate said drug-supply unit prior to the selected
gas-flow rate being reached, such that vapor is produced by said
unit in said chamber when said selected gas-flow rate is
reached.
12. The device of claim 1, wherein said actuation switch is
effective to activate said drug-supply unit when the selected
gas-flow rate is reached.
13. The device of claim 1, wherein said drug-supply unit includes
i. a heat-conductive substrate having an outer surface, ii. a film
of drug formed on said substrate surface, and iii. a heat source
for heating the substrate to a temperature effective to aid
drug,
14. The device of claim 13 wherein said drug delivery unit is
effective to vaporize the film of drug, following actuation, within
a period of less than 1 second.
15. The device of claim 14, wherein said drug delivery unit is
effective to vaporize the film of drug, following actuation, within
a period of less than 0.5 second.
Description
[0001] This application claims the benefit of U.S. provisional
application Ser. No. 60/429,776 filed Nov. 27, 2002, for "Method
and Apparatus for Controlling Flow of Gas over a Composition," and
U.S. provisional application Ser. No. 60/429,586, filed Nov. 27,
2002 for "Flow-Actuated Medical Device." Both of these applications
are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to an inhalation device for
producing desired-size drug-aerosol particles for inhalation.
BACKGROUND OF THE INVENTION
[0003] Therapeutic compounds may be administered by a variety of
routes, depending on the nature of the drug, the pharmacokinetic
profile desired, patient convenience, and cost, among other
factors. Among the most common routes of drug delivery are oral,
intravenous (IV), intramuscular (IM) intraperitoneal (IP)
subcutaneous, transdermal, transmucosal, and by inhalation to the
patient's respiratory tract.
[0004] The inhalation route of drug administration offers several
advantages for certain drugs, and in treating certain conditions.
Since the drug administered passes quickly from the respiratory
tract to the bloodstream, the drug may be active within a few
minutes of delivery. This rapid drug effect is clearly advantageous
for conditions like asthma, anaphylaxis, pain, and so forth where
immediate relief is desired.
[0005] Further, the drug is more efficiently utilized by the
patient, since the drug is taken up into the bloodstream without a
first pass through the liver as is the case for oral drug delivery.
Accordingly, the therapeutic dose of a drug administered by
inhalation can be substantially less, e.g., one half that required
for oral dosing.
[0006] Finally, since inhalation delivery is convenient, patient
compliance can be expected to be high.
[0007] As is known, efficient aerosol delivery to the lungs
requires that the particles have certain penetration and settling
or diffusional characteristics. For larger particles, deposition in
the deep lungs occurs by gravitational settling and requires
particles to have an effective settling size, defined as mass
median aerodynamic diameter (MMAD), of between 1-3.5 .mu.m. For
smaller particles, deposition to the deep lung occurs by a
diffusional process that requires having a particle size in the
10-100 nm, typically 20-100 nm range. Particle sizes that fall in
the range between 10-100 nm and 1-3.5 .mu.m tend to have poor
penetration and poor deposition. Therefore, an inhalation
drug-delivery device for deep lung delivery should produce an
aerosol having particles in one of these two size ranges.
[0008] Another important feature of an aerosol delivery device is
control over total dose delivered, that is, the amount of aerosol
generated should be predictable and repeatable from one dosing to
another.
[0009] Other desirable features for an inhalation device are good
product storageability, without significant loss of drug
activity.
[0010] It would therefore be desirable to provide an aerosol
inhalation device that provides these features in a simple, easily
operated inhalation device.
SUMMARY OF THE INVENTION
[0011] The invention includes a device for delivering a drug by
inhalation or by nasal administration, in an aerosol form composed
of drug-particles having desired sizes, typically expressed as mass
median aerodynamic diameter (MMAD) of the aerosol particles. The
device includes a body defining an interior flow-through chamber
having upstream and downstream chamber openings. A drug supply unit
contained within the chamber is designed for producing, upon
actuation, a heated drug vapor in a condensation region of the
chamber adjacent the substrate and between the upstream and
downstream chamber openings, such that gas drawn through the
chamber region at a selected gas-flow rate is effective to condense
drug vapor to form drug condensation particles having a selected
MMAD particle size, for example, when used for deep-lung delivery,
between 10-100 nm or between 1-3.5 .mu.m. To this end, the device
includes a gas-flow control valve disposed upstream of the
drug-supply unit for limiting gas-flow rate through the
condensation region to the selected gas-flow rate, for example, for
limiting air flow through the chamber as air is drawn by the user's
mouth into and through the chamber. Also included is an actuation
switch for actuating the drug-supply unit, such that the unit can
be controlled to produce vapor when the gas-flow rate through the
chamber is at the selected flow rate or within a selected flow-rate
range.
[0012] The actuation switch may activate the drug-supply unit such
that the unit is producing vapor when the selected air-flow rate is
achieved; alternatively, the actuation switch may activate the
drug-supply unit after the selected air-flow rate within the
chamber is reached.
[0013] In one general embodiment, the gas-flow valve is designed to
limit the rate of air flow through the chamber, as the user draws
air through the chamber by mouth. In a specific embodiment, the
gas-flow valve includes an inlet port communicating with the
chamber, and a deformable flap adapted to divert or restrict air
flow away from the port increasingly, with increasing pressure drop
across the valve. In another embodiment, the gas-flow valve
includes the actuation switch, with valve movement in response to
an air pressure differential across the valve acting to close the
switch. In still another embodiment, the gas-flow valve includes an
orifice designed to limit airflow rate into the chamber.
[0014] The device may also include a bypass valve communicating
with the chamber downstream of the unit for offsetting the decrease
in airflow produced by the gas-flow control valve, as the user
draws air into the chamber.
[0015] The actuation switch may include a thermistor that is
responsive to heat-dissipative effects of gas flow through the
chamber. The device may further include a user-activated switch
whose actuation is effective to heat the thermistor, prior to
triggering of the drug-supply unit by the thermistor to initiate
heating of the drug-supply unit.
[0016] The drug-supply unit may include a heat-conductive substrate
having an outer surface, a film of drug formed on the substrate
surface, and a heat source for heating the substrate to a
temperature effective to vaporize said drug. The heat source, may
be, for example, an electrical source for producing resistive
heating of the substrate, or a chemical heat source for producing
substrate heating by initiation of an exothermic reaction.
Preferably, the drug delivery unit is effective to vaporize the
film of drug, following actuation, within a period of less than 1
second, more preferably, within 0.5 seconds.
[0017] For producing condensation particles in the size range 1-3.5
.mu.m MMAD, the chamber may have substantially smooth-surfaced
walls, and the selected gas-flow rate may be in the range of 4-50
L/minute.
[0018] For producing condensation particles in the size range
20-100 nm MMAD, the chamber may provide gas-flow barriers for
creating air turbulence within the condensation chamber. These
barriers are typically placed within a few thousands of an inch
from the substrate surface.
[0019] These and other objects and features of the invention will
become more fully apparent when the following detailed description
of the invention is read in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a simplified sectional view of an inhalation
device constructed according to one embodiment of the
invention;
[0021] FIGS. 2A and 2B are plots of airflow rates through the
device of the invention, showing airflow through primary and
secondary flow regions, and the desired timing relationship between
airflow level and vaporization of drug;
[0022] FIG. 3 is a perspective, partially exploded view of the
device shown in FIG. 1;
[0023] FIG. 4A is a plot of aerosol condensation particle size
(MMAD) as a function of airflow rate in the absence of internal
turbulence for an airflow chamber having a cross-section area of 1
cm.sup.2, and at airflow rates between 5 and 30 liters/minute; and
FIG. 4B shows the fraction of alveolar deposition of aerosol
particles as a function of particle size;
[0024] FIGS. 5A-5F illustrate different types of gas-flow valves
suitable for use in the device of the invention;
[0025] FIGS. 6A-6C illustrate different types of actuation
circuitry suitable for use in the device of the invention;
[0026] FIGS. 7A-7E are photographic reproductions showing the
development of aerosol particles in the device over a period of
about 500 msec; and
[0027] FIGS. 8A-8C show alternative airflow control configurations
in the device of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0028] FIG. 1 is a simplified cross-sectional view of an inhalation
device 20 for delivering a drug by inhalation. The device includes
a body 22 defining an interior flow-through chamber 24 having
upstream and downstream chamber openings 26, 28, respectively. A
drug-supply unit 30 contained within the chamber is operable, upon
actuation, to produce a heated drug vapor in a condensation region
32 of the chamber adjacent the substrate and between the upstream
and downstream chamber openings. As will be detailed below, when
gas is flowed across the surface of the drug-supply unit, with
either laminar flow or with turbulence, at a selected velocity, the
drug vapor condenses to form drug condensation particles having a
selected MMAD particle size. As one of skill in the art would
appreciate, the gas velocity through the chamber may be controlled
by changing the volumetric gas-flow rate, cross-sectional area
within the chamber, and/or the presence or absence of structures
that produce turbulence within the chamber. For inhalation, two
exemplary size ranges are between about 1 and 3.5 .mu.m, and within
0.02 and 0.1 .mu.m.
[0029] The device includes a gas-flow control valve 34 disposed in
or adjacent the upstream opening of the chamber for limiting
gas-flow rate through the chamber's condensation region to a
selected gas-flow rate. Typically, the gas flowed through the
chamber is air drawn through the chamber by the user's mouth, that
is, by the user drawing air through the upstream end of the device
chamber. Various types of gas-flow valves suitable for use in the
invention are described below with respect to FIGS. 5A-5F.
[0030] Also included in the device is an actuation switch,
indicated generally at 36, for actuating the drug-supply unit. The
switch allows the drug-supply unit to be controlled to produce
vapor when the air-flow rate through the chamber's condensation
region is at the selected flow rate. As will be seen, the switch is
typically actuated by air flow through the chamber, such that as
the user draws air through the chamber, vapor production is
initiated when air flow through the condensation region reaches the
selected air flow rate for producing desired-size condensation
particles. Various types of activation switches suitable for use in
the invention are described below with respect to FIGS. 6A-6C.
[0031] In one general embodiment, the switch is constructed to
activate the drug-supply unit prior to the gas-flow rate in the
chamber reaching the selected rate. In this embodiment, the timing
of actuation is such that the drug-supply unit begins its
production of drug vapor at about the time or after the gas-flow
through the chamber reaches its selected gas-flow flow rate. In
another embodiment, the drug-supply unit is actuated when the
gas-flow rate through the chamber reaches the selected flow rate.
In yet another embodiment, the drug-supply unit is actuated at some
selected time after the selected flow rate has been reached.
[0032] The condensation region in the device, where heated drug
vapor is condensed to form desired-size aerosol particles, includes
that portion of the chamber between the drug-supply unit and the
interior wall of the chamber, and may include a portion of the
chamber between the downstream end of the drug-supply unit and the
downstream opening of the chamber. It is in this region where gas
flow is controlled to a desired rate and thus velocity during
aerosol formation.
[0033] As shown schematically in FIG. 1, drug-supply unit 30 in the
device generally includes a heat-conductive substrate 38 having an
outer surface 40, a film 42 of the drug to be administered formed
on the substrate's outer surface, and a heat source 44 for heating
the substrate to a temperature effective to vaporize the drug. In
the embodiment illustrated, the substrate is a tapered cylindrical
canister closed at its upstream end. A preferred material for the
substrate is stainless steel, which has been shown to be acceptable
for drug stability.
[0034] The drug film includes the drug to be administered either in
pure form, or mixed with suitable excipients. Exemplary drugs
suitable for use include any drugs that can be vaporized at a
temperature typically between 250-560.degree. C. The drug is
preferably one that can be vaporized with little or no
drug-degradation products. As has been reported in several co-owned
applications, many classes of drugs can be successfully vaporized
with little or no degradation, particularly where the drug coating
has a selected film thickness between about 0.01 and 10 .mu.m. The
amount of drug present is preferably sufficient to provide a
therapeutic dose, although the device may also be used to titrate a
therapeutic dose by multiple dosing. The total area of the
substrate on which the film is applied may be adjusted accordingly,
so that the total amount of drug available for aerosol formation
constitutes a therapeutic dose. Vaporization in typically less than
0.5 seconds is enabled by the thinness of the drug coating.
Essentially, the thin nature of the drug coating exposes a large
fraction of the heated compound to flowing air, resulting in almost
the entire compound vaporizing and cooling in the air prior to
thermal degradation. At film thicknesses used in the device,
aerosol particles having less than 5% degradation products are
produced over a broad range of substrate peak temperatures.
[0035] The heat source for vaporizing the drug may be a resistive
heating element, for example, the substrate itself, or resistive
wires placed against the interior surface of the substrate.
Alternatively, and as shown in FIG. 1, heat source 44 is a
chemically reactive material which undergoes an exothermic reaction
upon actuation, e.g., by a spark or heat element. In the particular
embodiment shown, actuation is produced by a spark supplied to the
upstream end of the chemical material, igniting an exothermic
reaction that spreads in a downstream to upstream direction within
the drug-supply unit, that is, in the direction opposite the flow
of gas within the chamber during aerosol formation. An exemplary
chemical material includes a mixture of Zr and MoO.sub.3, at a
weight ratio of about 75%:25%. The mixture may contain binders,
such as polyvinyl alcohol or nitrocellulose, and an initiator
comprising additives such as boron and KClO.sub.3, to control the
reaction. In any case, and as mentioned above, the material should
be formulated to produce complete heating over the substrate
surface in a period of 2 sec or less, preferably in the range
10-500 msec.
[0036] An exemplary peak temperature of the surface of the
drug-supply unit is 375.degree. C. The temperature can be modified
by changes in the fuel formulation. Because high drug purities are
obtained at temperatures higher than those needed for complete
vaporization, there may be a large window within which emitted dose
and aerosol purity are both high and consistent.
[0037] As noted above, actuation switch 36 in the device is
designed for actuating the drug-supply unit in relation to airflow
through the device chamber, such that the drug-supply unit produces
drug vapor when the air flow rate through the chamber is sufficient
for producing desired-size aerosol particles. In one general
embodiment, described below with respect to FIGS. 6A-6C, the switch
is controlled by airflow through the chamber, such that the
drug-supply unit is activated when (or just prior to, or after) the
rate of airflow in the device reaches its desired rate.
Alternatively, the switch may be user activated, allowing the user
to initiate drug vapor formation as air is being drawn into the
device. In the latter embodiment, the device may provide a signal,
such as an audible tone, to the user, when the desired rate of
airflow through the device is reached.
[0038] In the following discussion of gas-flow control through the
device, it will be assumed that the gas being drawn through the
device is air drawn in by the user's breath intake. However, it
will be appreciated that the gas, or a portion therefore, might be
supplied by a separate gas cartridge or source, such as a CO.sub.2
or nitrogen gas source. An inert or non-oxidizing gas may be
desirable, for example, in the vaporization of a drug that is
labile to oxidative breakdown at elevated temperature, that is,
during vaporization. In this case, the "gas" breathed in by the
user may be a combination of a pure gas supplied through the
condensation region, and air drawn in by the user downstream of the
condensation region, or may be just pure gas.
[0039] In the embodiment shown in FIG. 1, airflow between the
upstream and downstream ends of the device is controlled by both
gas-flow valve 34, which controls the flow of air into the upstream
opening of the device, and hence through the condensation region of
the chamber, and a bypass valve 46 located adjacent the downstream
end of the device. The bypass valve cooperates with the gas-control
valve to control the flow through the condensation region of the
chamber as well as the total amount of air being drawn through the
device.
[0040] In particular, and as seen in the air-flow plot in FIG. 2A,
the total volumetric airflow through the device, indicated at 1, is
the sum of the volumetric airflow rate P through valve 34, and the
volumetric airflow rate B through the bypass valve. Valve 34 acts
to limit air drawn into the device to a preselected level P, e.g.,
15 L/minute, corresponding to the selected air-flow rate for
producing aerosol particles of a selected size. Once this selected
airflow level is reached, additional air drawn into the device
creates a pressure drop across valve 46 which then accommodates
airflow through the valve into the downstream end of the device
adjacent the user's mouth. Thus, the user senses a full breath
being drawn in, with the two valves distributing the total airflow
between desired airflow rate P and bypass airflow rate B.
[0041] FIG. 2A also indicates the timing of the heating for the
drug-supply unit, wherein the time of heating is defined as the
time during which sufficient heat is applies to the drug substance
so as to cause rapid vaporization of the drug. As seen here,
heating time, indicated by the hatched rectangle, is intended to
occur within the period that the airflow P is at the desired
airflow rate, for example, within the time period indicated at
points a and b in the figure. It can be appreciated that if a user
draws in more or less breath, the difference in airflow rate is
accommodated by changes in B, with P remaining constant as long as
I is greater than P.
[0042] FIG. 2B shows the same gas-distribution effect, but plotted
as a series of flow profiles over five different time periods
during operation of the device. As seen here, the gas-flow rate
through the condensation region in the device, indicated at P in
the figure, remains relatively constant, while total gas-flow rate,
indicated at I increases over the first four time intervals, then
decreases.
[0043] The linear velocity of airflow over the vaporizing drug
affects the particle size of the aerosol particles produced by
vapor condensation, with more rapid airflow diluting the vapor such
that it condenses into smaller particles. In other words the
particle size distribution of the aerosol is determined by the
concentration of the compound vapor during condensation. This vapor
concentration is, in turn, determined by the extent to which
airflow over the surface of the heating substrate dilutes the
evolved vapor. As shown in FIG. 4A below, the particle size (MMAD)
remains well within an acceptable range (1-3.5 microns) at airflow
rates from 7 L/min to 28 L/min through the drug product. To achieve
smaller or larger particles, the gas velocity through the
condensation region of the chamber may be altered by (i) modifying
the gas-flow control valve to increase or decrease P, and/or (ii)
modifying the cross-section of the chamber condensation region to
increase or decrease linear gas velocity for a given volumetric
flow rate.
[0044] FIG. 4B shows the fraction of alveolar deposition of aerosol
particles as a function of particle size. As seen, maximum
deposition into the lungs occurs in either of two size ranges:
1-3.5 .mu.m or 20-100 nm. Therefore, where the device is employed
for drug delivery by inhalation, the selected gas-flow rate in the
device of a given geometry is such as to achieve aerosol particles
sizes in one of these two size ranges. One skilled in the art will
appreciate how changes in gas-flow velocity, to effect desired
particle sizes, can be achieved by manipulating volumetric gas-flow
rate, valve design and characteristics, cross-sectional area of the
condensation region of the device, and, particularly where small
particles are desired, placement of barriers within the chamber
capable of producing turbulence that increases the dilution effect
of gas flowing through the heated drug vapor.
[0045] FIG. 3 is an exploded view of device 20 illustrated in FIG.
1. Here the body of the device, indicated at 22, is formed of two
molded plastic members 48, 50 which are sealed together
conventionally. Bypass valves 46 are designed to be placed on
either side of a downstream end region 52 of the device, when the
two body members are sealed together. Member 48 includes an air
inlet 56 through which air is drawn into the device chamber
adjacent the upstream end of the device 54.
[0046] The drug-supply unit, air-intake valve, and actuation switch
in the device are all incorporated into a single assembly 58. The
parts of the assembly that are visible are the coated substrate 38,
gas control valve 34, battery housing 36 and a pull tab
(user-activated switch) 60 which extends through an opening at the
upstream end of the device body in the assembled device. An outer
flange 62 in the assembly is designed to fit in a groove 64 formed
on the inner wall of each member, partitioning the chamber into
upstream and downstream chamber sections 66, 68, respectively. The
flange has openings, such as opening 70, formed on its opposite
sides as shown, with each opening being gated by a gas-flow valve,
such as valve 34, for regulating the rate of airflow across the
valves. Thus, when air is drawn into the device by the user, with
the user's mouth on the upstream device end, air is drawn into the
device through intake 56 and into section 66. Valve 34 then
regulates airflow between the two chamber sections, as will be
described below with reference to FIGS. 5A-5F, to limit airflow
across the drug-supply device to the desired airflow rate P.
[0047] Turning to various gas-flow valve embodiments suitable for
the invention, FIG. 5A shows an umbrella valve 70. This valve is a
low-durometer rubber member 71 that flexes out of the way to allow
air to enter when the difference in pressure inside and outside of
the airway (between the upstream and downstream chamber sections).
This valve thus functions to "open" in response to an air pressure
differential across the valve, and is constructed so that the valve
limits airflow to the desired airflow rate in the device.
[0048] FIG. 5B illustrates a reed valve 72 that includes two
low-durometer rubber pieces 74 that are held together by a biasing
member 76 (such as a spring). When the air-pressure across the two
chamber sections reaches a selected differential, the two rubber
pieces pull apart to create an opening for air to flow into the
airway. Like valve 70, this valve thus functions to "open" in
response to an air pressure differential across the valve, and is
constructed so that the valve limits airflow to the desired airflow
rate in the device.
[0049] FIGS. 5C and 5D illustrate a valve 80 that bends in response
to a pressure differential across the chamber sections to let air
into the airway. Specifically, FIG. 5C illustrates this valve in an
extended closed position that does not allow any air into the
airway. One end portion of the valve is rigidly attached to a side
of a valve opening 84, with the opposite side of the valve
terminating against the side of an air-inlet opening 85. When the
difference in pressure between the inside and outside of the airway
passes a threshold level, the valve 80 bends at its center, and
rotates into the airway about the portion that stays rigidly
attached to the airway, as shown in FIG. 5D, creating the airway to
create an orifice for air to flow through the valve opening.
[0050] In construction, the lower flexing layers at 86 are formed
of flexible polymer plate material, while the upper short layers at
88 are formed of an inflexible polymer material. Also as shown, the
valve may include electrical contacts, such as contact 90, that are
brought into a closed circuit configuration when the valve is moved
to its open, deformed condition. Like the two valves above, valve
80 functions to "open" in response to an air pressure differential
across the valve, and is constructed so that in the open condition,
the valve limits airflow to the desired airflow rate in the
device.
[0051] The electrical switch in the valve may serve as a switching
member of the actuation switch, so that opening of the valve also
acts to actuate the drug-supply unit. The present invention
contemplates a gas-control valve that includes an electrical switch
that is moved from an open to closed condition, when the valve is
moved to a condition that admits airflow at the selected desired
rate.
[0052] FIGS. 5E and 5F illustrate a valve 92 that moves from an
open toward a partially closed condition as air is drawn into the
device. The valve includes a curved screened opening 94 having a
generally circular-arc cross section. A deformable valve flap 96
attached as shown at the top of the valve is designed to move
toward opening 94 as the pressure differential across the valve
increases, effectively closing a portion of the valve opening as
the air differential increases. The deformability of the flap, in
response to an air pressure differential across the valve, is such
as to maintain the desired air flow rate P through the valve
substantially independent of the pressure differential across the
valve. The valve differs from those described above in that the
valve is initially in an open condition, and moves progressively
toward a closed condition as the pressure differential across the
valve increases.
[0053] It will be appreciated that the bypass valve in the device
may have the same general construction as one of the valves noted
above, particular those valves that are designed to open when a
pressure differential is applied across the valve. The gas-control
and bypass valves are designed so that initial pressure
differential across the valves, when the user begins drawing air
into the device, is effective to first establish the desired flow
rate P through the condensation region in the device. Once this
flow rate is established, additional flow rate B applied by the
user is effective to "open" the bypass valve to allow bypass
airflow into the device. Since air is being drawn through the
device along both airflow paths, the user is unaware of the
bifurcation of airflow that occurs.
[0054] Exemplary actuation switches and associated circuitry
suitable for use in the invention are illustrated in FIGS. 6A-6C.
FIG. 6A illustrates a circuit 100 having a trigger switch 98 that
is connected between a voltage source 99 and microcontroller 102.
The trigger switch may be a valve-actuated switch, as above, or a
user activated switch that is activated during air intake. When the
trigger switch opens, the microcontroller no longer receives the
voltage from the voltage source. Accordingly, the microcontroller
senses the trigger event, and starts to measure (e.g., starts a
timer) the time that the trigger event lasts. If this trigger event
lasts at least the threshold time period t.sub.th, the
microcontroller closes a second switch 104 for a pulsing time
interval t.sub.p. This closing causes current flow from the voltage
source to a resistor 106 that is effective to either heat the
drug-substrate by resistive heating or to heat-initiate an
exothermic reaction in the drug-supply unit, shown at 108.
[0055] FIG. 6B illustrates another circuit 110 that can be used for
actuating the drug-supply unit, in accordance with the invention.
This circuit is similar to circuit 100, except that it operates to
pass a charge from a capacitor 112 to substrate 108. The capacitor
is typically charged by voltage source 99. The microcontroller 102
closes the normally open switch 113 when it detects that switch 98
has remained open for a threshold time period. The closing of
switch 113 transfers the charge from capacitor 112 to ground
through the substrate. The transferred charge is used either to
heat the substrate resistively, or to initiate an exothermic
reaction in the drug-supply unit as above.
[0056] Another exemplary actuation switch is illustrated at 114 in
FIG. 6C. This switch has a user-activated component which readies
the switch for use shortly before use, e.g., an air-flow responsive
component that activates the drug-supply unit when the desired
air-flow rate is achieved. The user-activated component is a
pull-tab switch 116 that is activated when the user pulls a tab
(tab 60 in the device illustrated in FIG. 3). When switch 116 is
closed, voltage source 118 is connected to a thermistor 122 which
is then heated to a temperature above ambient. The thermistor is
connected to a voltage comparator 120, such as a Seiko S-8143
comparator available from Seiko. The comparator functions to
measure the thermistor voltage output at a time shortly after the
user switch is activated. When a user then begins to draw air
across the thermistor, the airflow cause the thermistor to cool,
generating a different voltage output (by the thermistor). When the
difference in these voltages reaches a predetermined threshold, the
comparator signals a solid-state switch 124 to close, producing
current flow to drug-supply unit 108 from voltage source 118, and
activation of the unit. The heating of the thermistor and
comparator threshold are adjusted such that switch 124 is closed
when the air flow rate through the device reaches a desired airflow
rate.
[0057] The series of photographic reproductions in FIGS. 7A-7D
illustrate the time sequence of production of drug condensate
during operation of the device of the invention. At time 0 (FIG.
7A) when the drug-supply unit is first actuated, air flow is
established across the surface of the substrate, but no vapor has
yet been formed. At 50 msec (FIG. 7B), some condensate formation
can be observed downstream of the substrate. The amount of
condensate being formed increases up to about 200 msec, but is
still being formed at 500 msec, although the majority of condensate
has been formed in the first 500 msec.
[0058] FIGS. 8A-8C illustrate alternative device embodiments for
distributing airflow through the device during operation. In FIG.
8A, a device 126 includes an upstream opening 130 containing an
airflow sensor 132, such as the thermistor described above, which
is responsive to airflow through the opening. Air flow drawn into a
central chamber 134 by the user through opening 130 is valved, to
achieve a selected flow rate, by gas-flow control valve(s) 138.
Excess airflow is diverted to the downstream end region of the
chamber via a bypass channel 136 extending between the upstream and
downstream ends of the device, and communicating with central
chamber 134 through a valve 127. The orifice is so dimensioned that
drawing air into the device creates an initial pressure
differential across valve 138, so that airflow through the central
chamber reaches the desired airflow rate, with excess air being
diverted through the bypass orifice.
[0059] A device 142 shown in FIG. 8B has a similar airflow
configuration, but differs from device 126 in having only a single
valve 143 which functions to admit air into a central chamber 144
until a desired airflow rate is achieved, then divert excess air
into a bypass channel 145 that communicates with the downstream end
of the central chamber through an orifice as shown.
[0060] In the embodiment shown in FIG. 8C, and indicated at 146,
air is drawn into the upstream end of the central chamber 148
through an upstream orifice 149, and is drawn into the downstream
end of the chamber through a bypass orifice 150. The two orifices
are dimensioned so that air drawn into the device by the user
distributes at a predetermined ratio, corresponding roughly to the
desired ratio of P/B (see FIG. 2A) for a normal breath intake.
[0061] It will be appreciated from the above that the gas-control
valve in the device, and/or the bypass valve may include a valve
that has an active gas-control element, or may be an orifice
dimensioned to admit gas at a desired gas-flow rate, under
conditions of selected gas pressure differential.
[0062] From the forgoing, it can be appreciated how various objects
and features of the invention have been met. For use in drug
inhalation, the device reproducibly produces particles having
selected MMAD sizes either in the 1-3.5 .mu.m range, or in the
10-100 nm range, achieved by controlling air flow rates through the
device and the timing of airflow with respect to vapor production.
Because of the rapid vapor production, and where necessary, because
of the drug film thickness, the condensation particles are
substantially pure, i.e., free of degradation products. The device
is simple to operate, requiring little or no practice by the user
to achieve desired aerosol delivery, and relatively simple in
construction and operation.
[0063] Although the invention has been described with reference to
particular embodiments, it will be appreciated that various changes
and modifications may be made without departing from the
invention.
* * * * *